Genomic hallmarks and therapeutic implications of G0 cell cycle arrest in cancer

Author:

Wiecek Anna J.,Cutty Stephen J.,Kornai Daniel,Parreno-Centeno Mario,Gourmet Lucie E.,Tagliazucchi Guidantonio Malagoli,Jacobson Daniel H.,Zhang Ping,Xiong Lingyun,Bond Gareth L.,Barr Alexis R.,Secrier MariaORCID

Abstract

AbstractBackgroundTherapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative G0 state, which is difficult to capture and whose mutational drivers remain largely unknown.ResultsWe develop methodology to robustly identify this state from transcriptomic signals and characterise its prevalence and genomic constraints in solid primary tumours. We show that G0 arrest preferentially emerges in the context of more stable, less mutated genomes which maintainTP53integrity and lack the hallmarks of DNA damage repair deficiency, while presenting increased APOBEC mutagenesis. We employ machine learning to uncover novel genomic dependencies of this process and validate the role of the centrosomal geneCEP89as a modulator of proliferation and G0 arrest capacity. Lastly, we demonstrate that G0 arrest underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single-cell data.ConclusionsWe propose a G0 arrest transcriptional signature that is linked with therapeutic resistance and can be used to further study and clinically track this state.

Funder

Medical Research Foundation

Academy of Medical Sciences

Wellcome Trust

Biotechnology and Biological Sciences Research Council

Cancer Research UK

Publisher

Springer Science and Business Media LLC

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